Although the understanding of spinal cord injury (SCI) and its mechanisms have increased over the years, effective therapy to minimize tissue damage and maximize functional recovery remains a primary goal. The only treatment, methylprednisolone, has limited clinical efficacy. Emphasis is needed on early pharmacological intervention of secondary damage involving Ca2+ overload, free radicals, glutamate toxicity, and enzyme activation. Investigations into cell and fiber damage, tissue destruction, neuron protection, and maintenance of structural integrity are essential to effective treatments. After SCI, intracellular Ca2+ influx initiates secondary pathological events (cell damage, tissue destruction). Our goal is to protect CNS cells from secondary damage by using agents that preserve and restore function. Since several pathways cause cell damage and tissue destruction, multiple action drugs or a combination therapy will likely be more effective. One group of potential agents, steroid hormones, estrogen, and progesterone, are neuroprotective in cultured neurons and in CNS disorders. We hypothesize that estrogen/progesterone will control inflammatory processes, suppress intracellular Ca2+ levels, and inhibit Ca2+-dependent events. Suppression of intracellular Ca2+ will inhibit activation of lipases and proteinases (e.g., calpain) and protect cells from secondary damage. Estrogen decreases infiltration of inflammatory cells (e.g., macrophages), reduces Ca2+ levels and Ca2+-dependent events, and restores mitochondrial function in SCI lesion and penumbra (compared to vehicle-treated animals). Our preliminary data reveals that the effects seen with estrogen treatment may be superior to those seen with methylprednisolone. Cells undergoing apoptosis due to H202 and glutamate toxicity have increased intracellular Ca2+. Estrogen treatment reduced Ca2+, protected these cells from damage, and led to functional recovery. Thus, the following Specific Aims are proposed: . Examine the effects of estrogen treatment on inflammation following acute SCI . Investigate estrogen effects on intracellular Ca2+ influx and Ca2+ -dependent events in cell and tissue damage in SCI . Investigate whether estrogen treatment will preserve motor function in chronic SCI . Examine whether estrogen treatment will protect and preserve the function of neurons (cortical and motor) and glial cells subjected to oxidative stress and glutamate toxicity in culture. Novel and relevant techniques, i.e., determining Ca levels in cultured cells and SCI slices (fura-2), cell damage (TUNEL), cell function (electrophysiology), and motor recovery ("BBB" scale), will be used. Understanding estrogen's mechanisms in cell protection and recovery as it relates to multidestructive pathways will establish it as a viable SCI treatment agent.